PROJECT SUMMARY/ABSTRACT Multiple Sclerosis (MS), which may present with a relapsing-remitting (RR) or a primary progressive (PP) course, is the leading cause of neurologic disability in young adults. Despite clinical advances, one third of RRMS patients are non-responsive to current therapies, few drugs are available for PPMS, and there is no cure. MS pathogenesis is perpetuated by the cyclical reactivation and expansion of memory myelin-specific T helper (Th) cells that home to the Central Nervous System. Inflammatory T cells with Th1 and Th17 phenotype are pathogenic while regulatory (Treg) and Th2 cells are beneficial. Therefore, strategies that detect and curtail expansion of memory iTc while retaining bTc would provide a significant improvement in MS clinical management. We have recently discovered that a particular epigenetic modifier enzyme is a key molecular regulator of Th1 cell reactivation and Th cell phenotype and that manipulating its enzymatic activity could be therapeutic. We have developed first-in-class inhibitors specific for this enzyme at Ohio State University (patented) and selected two lead inhibitors that preferentially suppress memory Th1 vs. Th2 cell expansion, suppress Th17 cell differentiation and increase Tregs. In addition, a lead inhibitor suppressed pre-established EAE. Overall, these inhibitors have a desirable immunological profile to treat MS and other inflammatory autoimmune diseases. We hypothesize that enzyme activity triggers iTc responses while suppressing bTc responses, promoting clinical disease and propose to define the role of this enzyme as a predictor of disease course and the effects of select enzyme inhibitors on iTc over bTc populations in the EAE model of RR and PP MS. We will 1) determine the extent to which this specific enzyme activity modulates T cell responses and clinical disease in the relapsing-remitting (RR) and chronic Experimental Autoimmune Encephalomyelitis models of MS and 2) determine the extent to which the natural course of enzyme expression/activity predicts clinical disease pattern and severity in the RR and chronic Experimental Autoimmune Encephalomyelitis (EAE) mouse model of MS. These studies will determine whether targeting of this enzyme with small molecule inhibitor drugs is a viable approach to treat disease by suppressing myelin- specific inflammatory T cells. In addition, they will determine whether a stable or oscillating pattern of enzyme activity signals a chronic or relapsing-remitting disease course. Therefore, data from these experiments could be used to justify development of similar therapy and/or biomarker/therapy approaches for treating MS and other autoimmune diseases (e.g., diabetes, lupus).